Some Hope Seen in Negative IVIG Alzheimer Trial

by John Gever John Gever,Deputy Managing Editor, MedPage Today
July 16, 2013

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Action Points

Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that this randomized trial demonstrated no benefit to IVIG infusions among patients with Alzheimer's disease.

Additional studies of IVIG in patients who express the APOE4 risk allele will be needed to determine if the finding of IVIG benefit in this subgroup is more than a statistical aberation.

BOSTON -- Intravenous immunoglobulin (IVIG) is down but not out in Alzheimer's disease, as secondary analyses showed that APOE4 carriers benefited in an otherwise negative phase III trial, a researcher said here.

The 266 study participants with the epsilon-4 APOE gene variant who received high-dose IVIG in the 18-month trial showed significantly smaller declines in Modified Mini-Mental State Examination (3MS) scores than those receiving either a lower IVIG dose or placebo (difference 4.5 points, P=0.02), said Norman Relkin, MD, PhD, of Weill Cornell Medical College in New York City.

APOE4 carriers on high-dose IVIG also had better performance on three specific neuropsychological tests -- trailmaking, clock draw, and digit symbol substitution -- than those in the other two treatment groups, Relkin said at a press briefing held prior to his formal presentation at the Alzheimer's Association International Conference.

Relkin said that 3MS scores in the trial also showed a strong trend (P=0.07) toward a benefit with high-dose IVIG in participants with moderate impairment (baseline scores of 16 to 20), relative to the low-dose and placebo groups, but not in those with milder impairment (baseline scores of 21 to 26).

However, this finding was not replicated in the three specific neuropsychological tests.

Relkin also pointed to some intriguing biomarker findings that also suggested that IVIG did have an effect on patients, although perhaps it was not reflected in clinical outcomes.

There were dose-dependent decreases in the 42-amino acid form of beta-amyloid protein from baseline, he reported: -7.91 ng/mL with the high dose, -3.51 ng/mL with the low dose, and -1.35 ng/mL with placebo at 18 months.

Also, in 61 patients who underwent PET scans with the florbetapir (AmyVid) tracer for beta-amyloid plaques, there was a trend toward plaque clearance in the high-dose group that was especially strong in APOE4 carriers. However, patient numbers were too small for these to achieve statistical significance.

The GAP trial had randomized 390 patients to 400 or 200 mg/kg of IVIG or 0.25% human albumin (placebo) infused every two weeks for 18 months. Primary outcome measures were change from baseline in the Alzheimer's Disease Assessment Scale cognition score and the Alzheimer's Disease Cooperative Study's Activities of Daily Living scale.

Topline results had indicated only slight, nonsignificant differences between groups at the end of 18 months for both measures.

These results were a disappointment because an earlier, smaller phase II study reported at last year's AAIC meeting had shown a very strong benefit for IVIG. Relkin said at the press briefing that responders in that trial were still receiving IVIG and were still showing responses. "I'm not going to tell you they aren't progressing," he said, but the rate of progression has been "lower than expected."

He said the discordance between the phase II and phase III results were most likely "a statistical fluke."

Determining why APOE4 carriers showed better responses than noncarriers in the phase III study will require another study, Relkin suggested, in part because the GAP trial was underpowered to address it adequately.

He outlined three possible reasons for the difference. One is that it, too, was a statistical aberration.

Alternatively, he said, it could reflect more precise diagnoses. Relkin noted that Alzheimer's disease diagnoses in living patients is always uncertain, as the symptoms overlap considerably with other forms of dementia, and imaging scans for beta-amyloid plaques were only recently approved. Diagnoses of Alzheimer's disease are much more reliable in those with the APOE4 allele because it conveys a strong predisposition to the illness.

Yet another possibility is that Alzheimer's disease brain pathology in carriers differs from that in noncarriers, in a way that makes IVIG more effective.

Two preclinical studies described at the briefing reinforced the potential for IVIG as an Alzheimer's disease therapy.

In one, led by Scott Counts, PhD, of a Michigan State University lab in Grand Rapids, Mich., found that IVIG reduced tau protein accumulations -- the other major hallmark of Alzheimer's disease pathology besides amyloid plaques -- in mice engineered to overexpress tau proteins.

The other, led by Debomoy Lahiri, PhD, of Indiana University in Indianapolis, found that cultured human neurons were protected against oxidative damage when co-treated or pretreated with IVIG. Attack by reactive oxygen species is thought to be a major mechanism causing neuronal death in Alzheimer's disease and other neurodegenerative conditions.

Speaking of the GAP trial, Maria Carrillo, PhD, vice president of scientific and medical relations at the Alzheimer's Association, said the study was extremely valuable even though it didn't lead immediately to a new treatment.

"Biomarkers are of huge interest right now," she said, "and how biomarkers behave ... is still not well understood. We're still trying to figure out how to interpret biomarker results when they're embedded in clinical trials."

Relkin said the GAP group hoped to proceed with new studies of IVIG, but specific plans were still awaiting fuller analysis of the phase III results. He said his report here represented "the tip of the iceberg" regarding the analyses that could come out of the trial.

The trial was funded by Baxter and involved its proprietary IVIG product, GammaGard.

Relkin had relationships with Baxter, Eisai, and Kyowa Hakko Kirin. Other study investigators reported relationships with a large number of private companies, foundations, and government agencies.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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